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Abstract: Chemokines help facilitate the recruitment of inflammatory cells into tissues in response to infection or inflammation, and help coordinate the actions of the leukocytes that underlie an immune response. Animal models are the experimental tools of choice for the validation of chemokine biology and have provided much insight into the workings of chemokine biology. This review summarizes findings from chemokine research obtained through the application of animal models of pulmonary fibrosis, graft-versus-host disease, colitis, renal disease and allograft rejection. [Copyright &y& Elsevier]

Abstract: The interaction between a microorganism and a potential host may modify each other in multiple ways. Because of their central role in controlling leukocyte trafficking and activation, chemokines may be essential in defining these interactions. Here, we describe potential uses of intravital microscopy to define the role of chemokines and their receptors in the context of HSV-1 infection and EAE. We show that CCL5 plays a major role in driving neuropathology by mediating leukocyte adhesion and consequent migration in HSV-1 encephalitis. In contrast, CCR5 is important to attract cell types that modulate negatively CNS damage at the cost of allowing greater viral replication in the brain. Finally, intravital microscopy studies were crucial to determine that induction of leukocyte adhesion and subsequent emigration into the CNS is a major mechanism of action of CCL2 in EAE. [Copyright &y& Elsevier]

Abstract: The therapeutic effects of umbelliferone (30, 60 and 90 mg/kg), a coumarin isolated from Typha domingensis (Typhaceae) were investigated in a mouse model of bronchial asthma. BALB/c mice were immunized and challenged by nasal administration of ovalbumin. Treatment with umbelliferone (60 and 90 mg/kg) caused a marked reduction of cellularity and eosinophil numbers in bronchoalveolar lavage fluids from asthmatic mice. In addition, a decrease in mucus production and lung inflammation were observed in mice treated with umbelliferone. A reduction of IL-4, IL-5, and IL-13, but not of IFN-γ, was found in bronchoalveolar lavage fluids of mice treated with umbelliferone, similar to that observed with dexamethasone. The levels of ovalbumin-specific IgE were not significantly altered after treatment with umbelliferone. In conclusion, our results demonstrate that umbelliferone attenuates the alteration characteristics of allergic airway inflammation. The investigation of the mechanisms of action of this molecule may contribute for the development of new drugs for the treatment of asthma. [Copyright &y& Elsevier]

Abstract: Paracoccidioidomycosis (PCM) is the most common systemic mycosis in Latin America. A major problem in the management of PCM is to determine the best time to discontinue therapy due to the high relapse rate among patients. Soluble TNF receptors (sTNF-R) levels and chemokines are associated with disease activity in several infectious, inflammatory and autoimmune disorders. The aim of the present work was to evaluate levels of sTNF-R1, sTNF-R2 and chemokines in serum of patients with adult type of PCM, before and after antifungal therapy, and to correlate those levels to disease activity. Concentrations of sTNF-R1, sTNF-R2 and CXCL9 were higher in untreated patients and decreased progressively with treatment. The serum marker with the best accuracy to discriminate PCM cases from controls was sTNF-R2. sTNF-R1 did not drop to control levels before 36 months of treatment. CCL2 and CCL3 levels were low at baseline in PCM patients, raised significantly after 12 months of treatment and diminished thereafter. CCL24 levels were higher after 36 months of antifungal therapy in PCM patients. CCL11 levels were not statistically different from control subjects. sTNF-R1, sTNF-R2 and CXCL9 may be useful as laboratory parameters to assess disease activity in PCM patients. [Copyright &y& Elsevier]

Abstract: Background: Left ventricular dysfunction (LVd) is the main predictor of mortality in Chagas disease (ChD). Aims: To compare the diagnostic performance of the conventional approach (ECG and chest X-ray) in the recognition of LVd in ChD, with a new strategy, in which BNP is measured in patients with an abnormal ECG. Methods: Consecutive ChD patients recruited at an Outpatient Reference Center in Belo Horizonte, Brazil, without other systemic diseases, in 1998–99 (sample 1, n =165) and in 2001–02 (sample 2, n =62) underwent ECG, chest X-ray, BNP measurement and echocardiography. Results: The prevalence of LVd (ejection fraction ≤0.40) was 9.1% in the sample 1. The conventional strategy recognized all patients with LVd (sensitivity: 100%, 95% CI: 79.6–100% and negative predictive value −PV 100%, 92.1–100%), but with low specificity (30%, 95% CI: 23.2–37.8) and +PV (12.5%, 95% IC: I7.7–19.6). The BNP/ECG strategy showed significantly better specificity (96.0%, 95% CI: 91.5–98.2, p <0.001) and +PV (66.7%, 95% CI: 43.7–83.7, p <0.001), and non-significantly lower sensitivity (80.0%, 95% CI: 54.8–93.0, p =0.25) and −PV (98.0%,95% CI: 94.2–99.3, p =0.08). Overall accuracy was improved with the new strategy. (94.5%,95% CI: 90.0–97.1×36.4%, 95% CI: 29.4–43.9, p <0.001). Similar results were obtained for the sample 2. Conclusions: The BNP-based strategy was more accurate than the conventional approach in the detection of LVd in ChD patients and should be considered as a valid option. [Copyright &y& Elsevier]

Major advances have recently been achieved in the area of microbial recognition by the innate immune system. In this Forum, we discuss important issues related to innate recognition of bacteria and protozoan parasites. In particular, we highlight the structural characterization of pathogen-associated molecular patterns (PAMPs); the definition of the receptors required for recognition of PAMPs, especially the Toll-like receptors (TLRs); the signaling pathways triggered by PAMPs/PAMPs receptor interaction; and the functional consequences of these interactions for pathogenesis during microbial infection. [Copyright &y& Elsevier]

The inflammatory response that follows the infection with Trypanosoma cruzi is essential for host resistance to infection but is also responsible for the diverse pathology observed in Chagas disease. Here, we examine the stimuli and mechanisms underlying chemokine production following infection in vitro and in vivo, and the ability of chemokines to coordinate the influx of inflammatory and immune cells to the site of parasite infection, and to control T. cruzi growth. [Copyright &y& Elsevier]

Introduction: Pro‐resolving molecules may curb disease caused by viruses without altering the capacity of the host to deal with infection. AP1189 is a melanocortin receptor‐biased agonist endowed with pro‐resolving and anti‐inflammatory activity. We evaluated the preclinical and early clinical effects of treatment with AP1189 in the context of COVID‐19. Methods: C57BL/6j mice were infected intranasally with MHV‐A59 or hK18‐ACE2 mice with SARS‐CoV‐2. AP1189 (10 mg·kg−1, BID, s.c.) was given to the animals from day 2 and parameters evaluated at day 5. Human PBMCs from health donors were infected with SARS‐CoV‐2 in presence or absence of AP1189 and production of cytokines quantified. In the clinical study, 6 patients were initially given AP1189 (100 mg daily for 14 days) and this was followed by a randomized (2:1), placebo‐controlled, double‐blind trial that enrolled 54 hospitalized COVID‐19 patients needing oxygen support. The primary outcome was the time in days until respiratory recovery, defined as a SpO2 ≥ 93% in ambient air. Results: Treatment with AP1189 attenuated pulmonary inflammation in mice infected with MHV‐A59 or SARS‐CoV‐2 and decreased the release of CXCL10, TNF‐α and IL‐1β by human PBMCs. Hospitalized COVID‐19 patients already taking glucocorticoids took a median time of 6 days until respiratory recovery when given placebo versus 4 days when taking AP1189 (P = 0.017). Conclusion: Treatment with AP1189 was associated with less disease caused by beta‐coronavirus infection both in mice and in humans. This is the first demonstration of the effects of a pro‐resolving molecule in the context of severe infection in humans. [ABSTRACT FROM AUTHOR]

Objective: Pro-resolving molecules, including the peptide Angiotensin-(1–7) [Ang-(1–7)], have potential adjunctive therapy for infections. Here we evaluate the actions of Ang-(1–7) in betacoronavirus infection in mice. Methods: C57BL/6J mice were infected intranasally with the murine betacoronavirus MHV-3 and K18-hACE2 mice were infected with SARS-CoV-2. Mice were treated with Ang-(1–7) (30 µg/mouse, i.p.) at 24-, 36-, and 48-hours post-infection (hpi) or at 24, 36, 48, 72, and 96 h. For lethality evaluation, one additional dose of Ang-(1–7) was given at 120 hpi. At 3- and 5-days post- infection (dpi) blood cells, inflammatory mediators, viral loads, and lung histopathology were evaluated. Results: Ang-(1–7) rescued lymphopenia in MHV-infected mice, and decreased airways leukocyte infiltration and lung damage at 3- and 5-dpi. The levels of pro-inflammatory cytokines and virus titers in lung and plasma were decreased by Ang-(1–7) during MHV infection. Ang-(1–7) improved lung function and increased survival rates in MHV-infected mice. Notably, Ang-(1–7) treatment during SARS-CoV-2 infection restored blood lymphocytes to baseline, decreased weight loss, virus titters and levels of inflammatory cytokines, resulting in improvement of pulmonary damage, clinical scores and lethality rates. Conclusion: Ang-(1–7) protected mice from lung damage and death during betacoronavirus infections by modulating inflammation, hematological parameters and enhancing viral clearance. [ABSTRACT FROM AUTHOR]

Examines the capacity of phosphodiesterase type 4 (PDE4) inhibitors to exert anti-inflammatory actions. Discussion on the potential of this class of drugs to take their place as novel therapeutic agents for a variety of inflammatory diseases; Mechanisms of the anti-inflammatory action of PDE4 inhibitors; Clinical prospects. INSETS: Box 1. Possible mechanisms involved in the anti-inflammatory..;Chemical names..

The article reports that neutrophils are polymorphonuclear leukocytes that play a crucial role in acute infection. It notes that static and usual chemotaxis assays characterize chemoattractant molecules, adhesion molecules, and intracellular pathways necessary for neutrophil recruitment. Class I myosins are members of the myosin super family that bind to actin filaments and hydrolyze adenosine triphosphate to generate mechanical force.

Natural products (NPs) have long been used as a rich source of bioactive compounds for drug development. Recent technological advancements have revitalised natural products research as evidenced by increased publications in this field. In this editorial review, we highlight key points from the 2020 British Journal of Pharmacology (BJP) practical guide, which outlines standards for natural products research reports, and provide papers published in BJP between years 2020 to 2023 that demonstrate adherence to these guidelines. Looking ahead, we discuss the potential of chemical proteomics approaches to elucidate natural products mechanisms of action and identify therapeutic targets for future research. By fostering innovation, we aim to advance natural products research and contribute to the development of novel therapeutics that will have a significant impact on healthcare. [ABSTRACT FROM AUTHOR]

Immune status changes during pregnancy, with pro-inflammatory and anti-inflammatory contexts at different stages, making pregnant women potentially more susceptible to various infections. Infection by Zika virus during pregnancy can cause developmental damage to the fetus, and the altered immune response during pregnancy could contribute to disease during Zika infection. [ABSTRACT FROM AUTHOR]

In 2023, seventy novel drugs received market authorization for the first time in either Europe (by the EMA and the MHRA) or in the United States (by the FDA). Confirming a steady recent trend, more than half of these drugs target rare diseases or intractable forms of cancer. Thirty drugs are categorized as "first‐in‐class" (FIC), illustrating the quality of research and innovation that drives new chemical entity discovery and development. We succinctly describe the mechanism of action of most of these FIC drugs and discuss the therapeutic areas covered, as well as the chemical category to which these drugs belong. The 2023 novel drug list also demonstrates an unabated emphasis on polypeptides (recombinant proteins and antibodies), Advanced Therapy Medicinal Products (gene and cell therapies) and RNA therapeutics, including the first‐ever approval of a CRISPR‐Cas9‐based gene‐editing cell therapy. [ABSTRACT FROM AUTHOR]

Inflammation is generally accepted as a component of the host defence system and a protective response in the context of infectious diseases. However, altered inflammatory responses can contribute to disease in infected individuals. Many endogenous mediators that drive the resolution of inflammation are now known. Overall, mediators of resolution tend to decrease inflammatory responses and provide normal or greater ability of the host to deal with infection. In the lung, it seems that pro-resolution molecules, or strategies that promote their increase, tend to suppress inflammation and lung injury and facilitate control of bacterial or viral burden. Here, we argue that the demonstrated anti-inflammatory, pro-resolving, anti-thrombogenic and anti-microbial effects of such endogenous mediators of resolution may be useful in the treatment of the late stages of the disease in patients with COVID-19. [ABSTRACT FROM AUTHOR]

Microorganisms that cause pneumonia and translocate to the central nervous system (CNS) are responsible for high mortality worldwide. The fungus Cryptococcus gattii (Cg) and the bacteria Streptococcus pneumoniae (Sp) target the same infection organs. This study aimed to investigate the consequences of secondary Sp infection during murine cryptococcosis. Mice infected with Sp after Cg showed significantly increased lethality and a drop in scores of motor behaviour, neuropsychiatric status and autonomous function. Previous Cg infection favoured Sp multiplication in the lungs, causing intense inflammation and necrosis, with further increased bacterial translocation to the spleen, liver and brain. This phenotype was associated with increased platelet‐activating factor receptor (Pafr) gene expression, reduced M1 macrophage recruitment, and high levels of proinflammatory mediators. Strategies to overcome early mortality (i.e., infection of Pafr−/− mice, treatment with IL‐1 inhibitor or corticoid) were insufficient to revert this phenotype. These results suggest that Cg infection makes the lung microenvironment favourable for Sp colonization and dissemination. Altogether, it leads to an exacerbated and ineffective inflammatory response, decisive for the increased morbidity and mortality during coinfection. In conclusion, our results highlight the importance of more studies addressing coinfections and their consequences in the host, aiming to establish more effective therapeutical strategies. [ABSTRACT FROM AUTHOR]

Background: The co-circulation of flaviviruses in tropical regions has led to the hypothesis that immunity generated by a previous dengue infection could promote severe disease outcomes in subsequent infections by heterologous serotypes. This study investigated the influence of antibodies generated by previous Zika infection on the clinical outcomes of dengue infection. Methodology/Principal findings: We enrolled 1,043 laboratory confirmed dengue patients and investigated their prior infection to Zika or dengue. Severe forms of dengue disease were more frequent in patients with previous Zika infection, but not in those previously exposed to dengue. Conclusions/Significance: Our findings suggest that previous Zika infection may represent a risk factor for subsequent severe dengue disease, but we did not find evidence of antibody-dependent enhancement (higher viral titer or pro-inflammatory cytokine overexpression) contributing to exacerbation of the subsequent dengue infection. Author summary: Although dengue is a disease known for years in the world and has been affecting several continents, some aspects remain unclear. One of them is about the possible factors that may influence the development of severe forms of the disease. Much has been discussed about the influence of a previous dengue episode, but the global spreading of other flaviviruses to areas where dengue was already circulating has aroused interest regarding a role like the other dengue serotypes. In this sense, the recent spreading of the Zika virus has become a factor of interest. In this study, the prior Zika virus infection was associated with a higher frequency of more severe forms in subsequent dengue. Preliminary findings did not suggest that the mechanism is the same one triggered in secondary dengue, known as antibody-dependent enhancement. These findings are a stimulus to develop further research that can understand the potential mechanisms involved in the pathogenesis. [ABSTRACT FROM AUTHOR]

Septic arthritis is an inflammatory joint disease that is induced by pathogens such as Staphylococcus aureus. Infection of the joint triggers an acute inflammatory response directed by inflammatory mediators including microbial danger signals and cytokines and is accompanied by an influx of leukocytes. The recruitment of these inflammatory cells depends on gradients of chemoattractants including formylated peptides from the infectious agent or dying cells, host-derived leukotrienes, complement proteins and chemokines. Neutrophils are of major importance and play a dual role in the pathogenesis of septic arthritis. On the one hand, these leukocytes are indispensable in the first-line defense to kill invading pathogens in the early stage of disease. However, on the other hand, neutrophils act as mediators of tissue destruction. Since the elimination of inflammatory neutrophils from the site of inflammation is a prerequisite for resolution of the acute inflammatory response, the prolonged stay of these leukocytes at the inflammatory site can lead to irreversible damage to the infected joint, which is known as an important complication in septic arthritis patients. Thus, timely reduction of the recruitment of inflammatory neutrophils to infected joints may be an efficient therapy to reduce tissue damage in septic arthritis. [ABSTRACT FROM AUTHOR]

The pro-inflammatory chemokine interleukin-8 (CXCL8) exerts its function by establishing a chemotactic gradient in infected or damaged tissues to guide neutrophil granulocytes to the site of inflammation via its G protein-coupled receptors (GPCRs) CXCR1 and CXCR2 located on neutrophils. Endothelial glycosaminoglycans (GAGs) have been proposed to support the chemotactic gradient formation and thus the inflammatory response by presenting the chemokine to approaching leukocytes. In this study, we show that neutrophil transmigration in vitro can be reduced by adding soluble GAGs and that this process is specific with respect to the nature of the glycan. To further investigate the GAG influence on neutrophil migration, we have used an engineered CXCL8 mutant protein (termed PA401) which exhibits a much higher affinity towards GAGs and an impaired GPCR activity. This dominant-negative mutant chemokine showed anti-inflammatory activity in various animal models of neutrophil-driven inflammation, i.e. in urinary tract infection, bleomycin-induced lung fibrosis, and experimental autoimmune uveitis. In all cases, treatment with PA401 resulted in a strong reduction of transmigrated inflammatory cells which became evident from histology sections and bronchoalveolar lavage. Since our CXCL8-based decoy targets GAGs and not GPCRs, our results show for the first time the crucial involvement of this glycan class in CXCL8/neutrophil-mediated inflammation and will thus pave the way to novel approaches of anti-inflammatory treatment. [ABSTRACT FROM AUTHOR]

Macrophages are important effectors of inflammation resolution that contribute to the elimination of pathogens and apoptotic cells and restoration of homeostasis. Pre-clinical studies have evidenced the anti-inflammatory and pro-resolving actions of GILZ (glucocorticoid-induced leucine zipper). Here, we evaluated the role of GILZ on the migration of mononuclear cells under nonphlogistic conditions and Escherichia coli-evoked peritonitis. TAT-GILZ (a cell-permeable GILZ-fusion protein) injection into the pleural cavity of mice induced monocyte/macrophage influx alongside increased CCL2, IL-10 and TGF-β levels. TAT-GILZ-recruited macrophages showed a regulatory phenotype, exhibiting increased expression of CD206 and YM1. During the resolving phase of E. coli-induced peritonitis, marked by an increased recruitment of mononuclear cells, lower numbers of these cells and CCL2 levels were found in the peritoneal cavity of GILZ-deficient mice (GILZ−/−) when compared to WT. In addition, GILZ−/− showed higher bacterial loads, lower apoptosis/efferocytosis counts and a lower number of macrophages with pro-resolving phenotypes. TAT-GILZ accelerated resolution of E. coli-evoked neutrophilic inflammation, which was associated with increased peritoneal numbers of monocytes/macrophages, enhanced apoptosis/efferocytosis counts and bacterial clearance through phagocytosis. Taken together, we provided evidence that GILZ modulates macrophage migration with a regulatory phenotype, inducing bacterial clearance and accelerating the resolution of peritonitis induced by E. coli. [ABSTRACT FROM AUTHOR]

Leukocyte recruitment to tissues is a highly orchestrated process and is one of the pillars of the inflammatory process. The contribution of leukocytes to tissue damage is very clear, suggesting that targeting leukocyte accumulation in tissue to be relevant for the development of novel therapies to treat chronic inflammatory diseases. Here, we review briefly known mechanisms of leukocyte recruitment and suggest potential targets for the development of novel anti-inflammatory therapies. [ABSTRACT FROM AUTHOR]

Dengue disease is a major problem worldwide, impacting millions of people annually with no specific approved treatments. The pathogenesis of dengue is a complex interplay of viral and host factors, driven in particular by an excessive inflammatory response triggered by the infection. While it has been observed that various viruses can modulate the PI3K/Akt signaling pathway to aid replication and theunderlying mechanisms remainunclear. The study aims to explore the impact of PI3Kγ inhibition during Dengue virus (DENV) infection in vivo. Experiments were performed using both wild-type (WT) and PI3Kγ knockout mice inoculated with DENV. Parameters, including survival rates, hematologic, virologic, histopathologic, and inflammatory analyzes, were evaluated. Additionally, the therapeutic potential of a selective PI3Kγ inhibitor (AS605240) was investigated in DENV-infected A129 mice. PI3Kγ deficiency resulted in lower lethality and provided protection against DENV-induced thrombocytopenia, decreased hemoconcentration, vascular permeability, and liver damage compared to DENV-infected WT littermates. In addition, PI3Kγ deficiency correlated with reduced viral replication in the blood, spleen and liver alongside decreased production of inflammatory mediators in plasma and spleen. Pharmacologic inhibition of PI3Kγ not only ameliorated DENV-induced thrombocytopenia and liver injury, but also reduced DENV replication in target organs. Treatment with AS605240 reduced the concentration of IL-6 in the spleen and plasma.This study sheds light on the significant pro-viral effects of the PI3Kγ signaling pathway during DENV infection and its central role in pathogenesis by curbing excessive DENV-induced inflammation. Inhibition of PI3Kγ shows promising host-directed target for developing novel Dengue disease therapies, offering substantial benefits to hosts. • Activation of the PI3Kγ signaling pathway during DENV infection contributes to the pathogenesis. • PI3Kγ deficiency protects mice from lethality and thrombocytopenia induced by DENV infection. • Inhibition of PI3Kγ decrease viral load, production of inflammatory mediators and liver damage. • PI3Kγ represents promising host-specific target to treat Dengue disease. [ABSTRACT FROM AUTHOR]

Background and Purpose: Gouty arthritis is characterized by an intense inflammatory response to monosodium urate crystals (MSU), which induces severe pain. Current therapies are often ineffective in reducing gout-related pain. Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator with anti-inflammatory and analgesic proprieties. In this study, we evaluated the effects and mechanisms of action of RvD1 in an experimental mouse model of gouty arthritis, an aim that was not pursued previously in the literature.Experimental Approach: Male mice were treated with RvD1 (intrathecally or intraperitoneally) before or after intraarticular stimulation with MSU. Mechanical hyperalgesia was assessed using an electronic von Frey aesthesiometer. Leukocyte recruitment was determined by knee joint wash cell counting and immunofluorescence. IL-1β production was measured by ELISA. Phosphorylated NF-kB and apoptosis-associated speck-like protein containing CARD (ASC) were detected by immunofluorescence, and mRNA expression was determined by RT-qPCR. CGRP release was determined by EIA and immunofluorescence. MSU crystal phagocytosis was evaluated by confocal microscopy.Key Results: RvD1 inhibited MSU-induced mechanical hyperalgesia in a dose- and time-dependent manner by reducing leukocyte recruitment and IL-1β production in the knee joint. Intrathecal RvD1 reduced the activation of peptidergic neurons and macrophages as well as silenced nociceptor to macrophage communication and macrophage function. CGRP stimulated MSU phagocytosis and IL-1β production by macrophages. RvD1 downmodulated this phenomenon directly by acting on macrophages, and indirectly by inhibiting CGRP release and CGRP-dependent activation of macrophages.Conclusions and Implications: This study reveals a hitherto unknown neuro-immune axis in gouty arthritis that is targeted by RvD1. [ABSTRACT FROM AUTHOR]

Chikungunya (CHIKV) is an arthritogenic alphavirus that causes a self-limiting disease usually accompanied by joint pain and/or polyarthralgia with disabling characteristics. Immune responses developed during the acute phase of CHIKV infection determine the rate of disease progression and resolution. Annexin A1 (AnxA1) is involved in both initiating inflammation and preventing over-response, being essential for a balanced end of inflammation. In this study, we investigated the role of the AnxA1-FPR2/ALX pathway during CHIKV infection. Genetic deletion of AnxA1 or its receptor enhanced inflammatory responses driven by CHIKV. These knockout mice showed increased neutrophil accumulation and augmented tissue damage at the site of infection compared with control mice. Conversely, treatment of wild-type animals with the AnxA1 mimetic peptide (Ac2–26) reduced neutrophil accumulation, decreased local concentration of inflammatory mediators and diminished mechanical hypernociception and paw edema induced by CHIKV-infection. Alterations in viral load were mild both in genetic deletion or with treatment. Combined, our data suggest that the AnxA1-FPR2/ALX pathway is a potential therapeutic strategy to control CHIKV-induced acute inflammation and polyarthralgia. [ABSTRACT FROM AUTHOR]

Scientists who plan to publish in British Journal of Pharmacology (BJP) must read this article before undertaking a study. This editorial provides guidance for the design of experiments. We have published previously two guidance documents on experimental design and analysis (Curtis et al., 2015; Curtis et al., 2018). This update clarifies and simplifies the requirements on design and analysis for BJP manuscripts. This editorial also details updated requirements following an audit and discussion on best practice by the BJP editorial board. Explanations for the requirements are provided in the previous articles. Here, we address new issues that have arisen in the course of handling manuscripts and emphasise three aspects of design that continue to present the greatest challenge to authors: randomisation, blinded analysis and balance of group sizes. [ABSTRACT FROM AUTHOR]

Chagas cardiomyopathy is the most severe and life-threatening manifestation of human Chagas disease--a 'neglected' tropical disease caused by the protozoan parasite Trypanosoma cruzi. The disease is endemic in all continental Latin American countries, but has become a worldwide problem because of migration of infected individuals to developed countries, mainly in Europe and North America. Chagas cardiomyopathy results from the combined effects of persistent parasitism, parasite-driven tissue inflammation, microvascular and neurogenic dysfunction, and autoimmune responses triggered by the infection. Clinical presentation varies widely according to the extent of myocardial damage, and manifests mainly as three basic syndromes that can coexist in an individual patient: heart failure, cardiac arrhythmia, and thromboembolism. NYHA functional class, left ventricular systolic function, and nonsustained ventricular tachycardia are important prognostic markers of the risk of death. Management of Chagas cardiomyopathy focuses on the treatment of the three main syndromes. The use of β-blockers in patients with Chagas disease and heart failure is safe, well tolerated, and should be encouraged. Most specialists and international institutions now recommend specific antitrypanosomal treatment of patients with chronic Chagas disease, even in the absence of evidence obtained from randomized clinical trials. Further research on the management of patients with Chagas cardiomyopathy is necessary. [ABSTRACT FROM AUTHOR]

Human infection with the protozoan parasite Trypanosoma cruzi leads to Chagas disease, which affects ∼17 million people in Latin America. A significant percentage of the infected population will develop clinical symptoms or present changes in laboratory and/or image evaluation. The existence of a large spectrum of clinical manifestations – with patients ranging from asymptomatic to severe cardiac involvement – emphasizes the need to use standardized and well-defined clinical criteria among different research groups. In this article, we carry out a systematic review of the immunology in human Chagas disease, discussing recent findings in the context of a clinical perspective. [Copyright &y& Elsevier]

Background: Arboviruses transmitted by Aedes aegypti including dengue, Zika, and chikungunya are a major global health problem, with over 2.5 billion at risk for dengue alone. There are no licensed antivirals for these infections, and safe and effective vaccines are not yet widely available. Thus, prevention of arbovirus transmission by vector modification is a novel approach being pursued by multiple researchers. However, the field needs high-quality evidence derived from randomized, controlled trials upon which to base the implementation and maintenance of vector control programs. Here, we report the EVITA Dengue trial design (DMID 17-0111), which assesses the efficacy in decreasing arbovirus transmission of an innovative approach developed by the World Mosquito Program for vector modification of Aedes mosquitoes by Wolbachia pipientis.Methods: DMID 17-0111 is a cluster-randomized trial in Belo Horizonte, Brazil, with clusters defined by primary school catchment areas. Clusters (n = 58) will be randomized 1:1 to intervention (release of Wolbachia-infected Aedes aegypti mosquitoes) vs. control (no release). Standard vector control activities (i.e., insecticides and education campaigns for reduction of mosquito breeding sites) will continue as per current practice in the municipality. Participants (n = 3480, 60 per cluster) are children aged 6-11 years enrolled in the cluster-defining school and living within the cluster boundaries who will undergo annual serologic surveillance for arboviral infection. The primary objective is to compare sero-incidence of arboviral infection between arms.Discussion: DMID 17-0111 aims to determine the efficacy of Wolbachia-infected mosquito releases in reducing human infections by arboviruses transmitted by Aedes aegypti and will complement the mounting evidence for this method from large-scale field releases and ongoing trials. The trial also represents a critical step towards robustness and rigor for how vector control methods are assessed, including the simultaneous measurement and correlation of entomologic and epidemiologic outcomes. Data from this trial will inform further the development of novel vector control methods.Trial Registration: ClinicalTrials.gov NCT04514107 . Registered on 17 August 2020 Primary sponsor: National Institute of Health, National Institute of Allergy and Infectious Diseases. [ABSTRACT FROM AUTHOR]

Mucositis is a major clinical complication associated with cancer treatment and may limit the benefit of chemotherapy. Leukocytes and inflammatory mediators have been extensively associated with mucositis severity. However, the role of eosinophils in the pathophysiology of chemotherapy‐induced mucositis remains to be elucidated. Here, using GATA‐1‐deficient mice, we investigated the role of eosinophils in intestinal mucositis. There was marked accumulation of eosinophils in mice given irinotecan and eosinophil ablation inhibited intestinal mucositis. Treatment with Evasin‐4, a chemokine receptor antagonist, reduced the recruitment of eosinophils and decreased irinotecan‐induced mucositis. Importantly, Evasin‐4 did not interfere negatively with the antitumour effects of irinotecan. Evasin‐4 was of benefit for mice given high doses of irinotecan once Evasin‐4‐treated mice presented delayed mortality. Altogether, our findings suggest that Evasin‐4 may have significant mucosal‐protective effects in the context of antineoplastic chemotherapy and may, therefore, be useful in combination with anticancer treatment in cancer patients. [ABSTRACT FROM AUTHOR]

Angiogenesis and inflammation play critical roles in tumor growth. Using an in vivo tumor model, we report that thalidomide (100 mg kg(-1)day(-1)) or clotrimazole (120 mg kg(-1) day(-1)), inhibit blood vessel formation (determined by hemoglobin content), leukocyte recruitment [myeloperoxidase (MPO) activity; N-acetylglucosa-minidase (NAG) activity], and vascular endothelial growth factor production. Inhibition of angiogenesis ranged from 35% to 65%. Clotrimazole was the most potent antiangiogenic compound and the agent capable of inhibiting tumor growth. Thalidomide was able to reduce the inflammatory reaction (MPO and NAG activities) by 50% to 70%, but was unable to delay tumor development. These results suggest that for this type of solid tumor the degree of neovascularization, rather than inhibition of inflammatory cell recruitment, is a determinant factor in tumor development. As the contribution of angiogenesis and inflammation to cancer progression vary markedly among different tumor types, it may be relevant to consider these factors in cancer therapy using antiangiogenesis/antiinflammatory approaches. [ABSTRACT FROM AUTHOR]

Gout is an inflammatory disease triggered by deposition of monosodium urate (MSU) crystals in the joints, resulting in high neutrophil influx and pain. Here, we studied the role of the inhibitory receptor CD300a in the resolution process in a murine model of gout. We found increased CD300a expression on neutrophils emigrated to the joint. When compared to WT mice, CD300a−/− mice had persistent neutrophil influx till 24 hr after MSU injection. This was associated with increased concentration of IL‐1β and greater tissue damage in the joints of CD300a−/− mice. There was an increase in the percentage of apoptotic neutrophils in the synovial lavage of WT mice, as compared to CD300a−/− mice. This difference was reflected in the decline of efferocytic events in the synovial cavity of CD300a−/− mice 24 hr after MSU injection. A CD300a agonistic antibody was shown, for the first time, to increase apoptosis of human neutrophils, and this was associated with cleavage of caspase‐8. In conclusion, our results reveal an important role of CD300a in the control of leucocyte infiltration, IL‐1β production and caspase‐8 cleavage in neutrophils, contributing to the resolution of inflammation triggered by MSU injection. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) infection of neurons leads to neurological complications and congenital malformations of the brain of neonates. To date, ZIKV mechanism of infection and pathogenesis is not entirely understood and different studies on gene regulation of ZIKV-infected cells have identified a dysregulation of inflammatory and stem cell maintenance pathways. MicroRNAs (miRNAs) are post-transcriptional regulators of cellular genes and they contribute to cell development in normal function and disease. Previous reports with integrative analyses of messenger RNAs (mRNAs) and miRNAs during ZIKV infection have not identified neurological pathway defects. We hypothesized that dysregulation of pathways involved in neurological functions will be identified by RNA profiling of ZIKV-infected fetal neurons. We therefore used microarrays to analyze gene expression levels following ZIKV infection of fetal murine neurons. We observed that the expression levels of transcription factors such as neural PAS domain protein 4 (Npas4) and of three members of the orphan nuclear receptor 4 (Nr4a) were severely decreased after viral infection. We confirmed that their downregulation was at both the mRNA level and at the protein level. The dysregulation of these transcription factors has been previously linked to aberrant neural functions and development. We next examined the miRNA expression profile in infected primary murine neurons by microarray and found that various miRNAs were dysregulated upon ZIKV infection. An integrative analysis of the differentially expressed miRNAs and mRNAs indicated that miR-7013-5p targets Nr4a3 gene. Using miRmimics, we corroborated that miR-7013-5p downregulates Nr4a3 mRNA and protein levels. Our data identify a profound dysregulation of neural transcription factors with an overexpression of miR-7013-5p that results in decreased Nr4a3 expression, likely a main contributor to ZIKV-induced neuronal dysfunction. Author summary: Zika virus (ZIKV) is an emerging virus transmitted horizontally between humans through mosquito bites, and sexual intercourse generally inducing a mild disease. ZIKV is also transmitted vertically from mother-to-child producing congenital ZIKV syndrome (CZVS) in neonates. CZVS leads to severe microcephaly associated with neurological, ocular, musculoskeletal, genitourinary disorders and other disabilities. Although numerous studies have been performed on ZIKV infection of brain cells, we are still far from understanding how ZIKV infection leads to dysregulation of host genes, virus-induced cytopathicity and consequent pathology. Micro (mi)RNAs are small noncoding RNAs encoded and processed by the host cell. They regulate gene expression at the post-transcriptional level in a process called RNA interference (RNAi). Here, we evaluated the relationship between ZIKV infection and the level of mRNAs and miRNAs expressed in the cell. ZIKV infection of mouse embryo neurons downregulated several neural immediate-early genes (IEG). Moreover, we revealed that ZIKV infection led to aberrant regulation of several miRNAs, and identified one whose cognate target was a neural IEG. Our work identifies novel genes and miRNAs that are modulated upon ZIKV infection of fetal murine neurons, therefore linking neuronal dysfunction to transcription and the RNA interference pathway. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of IL-33 in gouty arthritis. Material: 174 Balb/c (wild-type) and 54 ST2−/− mice were used in this study. In vitro experiments were conducted in bone marrow-derived macrophages (BMDMs). Synovial fluid samples from gouty arthritis (n = 7) and osteoarthritis (n = 8) hospital patients were used to measure IL-33 and sST2 levels. Methods: Gout was induced by injection of monosodium urate (MSU) crystals in the knee joint of mice. Pain was determined using the electronic von Frey and static weight bearing. Neutrophil recruitment was determined by H&E staining, Rosenfeld staining slides, and MPO activity. ELISA was used for cytokine and sST2 measurement. The priming effect of IL-33 was determined in BMDM. Results: Synovial fluid of gout patients showed higher IL-33 levels and neutrophil counts than osteoarthritis patients. In mice, the absence of ST2 prevented mechanical pain, knee joint edema, neutrophil recruitment to the knee joint, and lowered IL-1β and superoxide anion levels. In macrophages, IL-33 enhanced the release of IL-1β and TNF-α, and BMDMs from ST2−/− showed reduced levels of these cytokines after stimulus with MSU crystals. Conclusion: IL-33 mediates gout pain and inflammation by boosting macrophages production of cytokines upon MSU crystals stimulus. [ABSTRACT FROM AUTHOR]

Endothelial nitric oxide synthase (eNOS) malfunctioning has been proposed to contribute to the endothelial damage produced by cigarette. Besides eNOS, neuronal NOS (nNOS) is also expressed in most vascular tissues and plays an important role in the endothelium-dependent vascular relaxation. We hypothesize that nNOS may contribute to the endothelium dysfunction produced by cigarette in smokers. Vascular function was assessed in human resistance mesenteric arteries using a wire myograph, the level of protein expression by Western blot, eNOS and nNOS localization by immunofluorescence. Measurement of NO was assessed by fluorescence microscopy. Arteries of smokers showed impaired endothelium-dependent vascular relaxation in response to acetylcholine. Pharmacological nonselective blockade of NOS with l -NAME and selective nNOS blockade with inhibitor 1 reduced the relaxation of the mesenteric artery of both smokers and nonsmokers. Interestingly, the inhibitory effect of NOS inhibitors was greater in nonsmokers than in smokers. The expression of total nNOS and eNOS and the level of phosphorylation at eNOS-pSer1177 were reduced in arteries of smokers as compared with nonsmokers. No differences between groups were observed in the expression of total COX-1, COX-2, catalase and SOD-1. Immunofluorescence analysis showed the presence of nNOS in the vascular endothelium in both groups. Acetylcholine-induced NO production was impaired in arteries from smokers as compared to nonsmokers. Selective inhibition of nNOS caused a decreased in NO production, which was greater in nonsmokers than in smokers. Our data show that a decrease in nNOS expression contributes to the endothelial dysfunction caused by cigarette smoking in human. • The role of nNOS in endothelial dysfunction caused by cigarette smoking is unknown. • Chronic smoking causes NO impairment and endothelial dysfunction in human mesenteric arteries. • Chronic smoking decreases nNOS expression in human mesenteric arteries. • Decreased nNOS expression contributes to the endothelial dysfunction caused by smoking. [ABSTRACT FROM AUTHOR]

Summary: Annexins are well‐known Ca2+ phospholipid‐binding proteins, which have a wide variety of cellular functions. The role of annexin A1 (AnxA1) in the innate immune system has focused mainly on the anti‐inflammatory and proresolving properties through its binding to the formyl‐peptide receptor 2 (FPR2)/ALX receptor. However, studies suggesting an intracellular role of AnxA1 are emerging. In this study, we aimed to understand the role of AnxA1 for interleukin (IL)‐1β release in response to activators of the nucleotide‐binding domain leucine‐rich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3) inflammasome. Using AnxA1 knockout mice, we observed that AnxA1 is required for IL‐1β release in vivo and in vitro. These effects were due to reduction of transcriptional levels of IL‐1β, NLRP3 and caspase‐1, a step called NLRP3 priming. Moreover, we demonstrate that AnxA1 co‐localize and directly bind to NLRP3, suggesting the role of AnxA1 in inflammasome activation is independent of its anti‐inflammatory role via FPR2. Therefore, AnxA1 regulates NLRP3 inflammasome priming and activation in a FPR2‐independent manner. [ABSTRACT FROM AUTHOR]

Inflammation triggered by influenza A virus (IAV) infection is important for viral clearance, induction of adaptive responses, and return to lung homeostasis. However, an exaggerated immune response, characterized by the overproduction of chemokines, can lead to intense lung injury, contributing to mortality. Chemokine scavenger receptors, such as ACKR2, control the levels of CC chemokines influencing the immune responses. Among the chemokine targets of ACKR2, CCL5 is important to recruit and activate lymphocytes. We investigated the role of ACKR2 during IAV infection in mice. Pulmonary ACKR2 expression was increased acutely after IAV infection preceding the virus-induced lung dysfunction. ACKR2-knockout (ACKR2-/-) mice were protected from IAV, presenting decreased viral burden and lung dysfunction. Mechanistically, the absence of ACKR2 resulted in augmented airway CCL5 levels, secreted by mononuclear and plasma cells in the lung parenchyma. The higher chemokine gradient led to an augmented recruitment of T and B lymphocytes, formation of inducible bronchus-associated lymphoid tissue and production of IgA in the airways of ACKR2-/- mice post-IAV. CCL5 neutralization in ACKR2-/- mice prevented lymphocyte recruitment and increased bronchoalveolar lavage fluid protein levels and pulmonary dysfunction. Finally, CCR5-/- mice presented increased disease severity during IAV infection, displaying increased neutrophils, pulmonary injury and dysfunction, and accentuated lethality. Collectively, our data showed that ACKR2 dampens CCL5 levels and the consequent recruitment of CCR5+ T helper 1 (Th1), T regulatory cells (Tregs), and B lymphocytes during IAV infection, decreasing pathogen control and promoting lung dysfunction in wild type mice. Therefore, ACKR2 is detrimental and CCR5 is protective during IAV infection coordinating innate and adaptive immune responses in mice. [ABSTRACT FROM AUTHOR]

Macrophages are central to inflammation resolution, an active process aimed at restoring tissue homeostasis following an inflammatory response. Here, the effects of db-cAMP on macrophage phenotype and function were investigated. Injection of db-cAMP into the pleural cavity of mice induced monocytes recruitment in a manner dependent on PKA and CCR2/CCL2 pathways. Furthermore, db-cAMP promoted reprogramming of bone-marrow-derived macrophages to a M2 phenotype as seen by increased Arg-1/CD206/Ym-1 expression and IL-10 levels (M2 markers). Db-cAMP also showed a synergistic effect with IL-4 in inducing STAT-3 phosphorylation and Arg-1 expression. Importantly, db-cAMP prevented IFN-γ/LPS-induced macrophage polarization to M1-like as shown by increased Arg-1 associated to lower levels of M1 cytokines (TNF-α/IL-6) and p-STAT1. In vivo, db-cAMP reduced the number of M1 macrophages induced by LPS injection without changes in M2 and Mres numbers. Moreover, db-cAMP enhanced efferocytosis of apoptotic neutrophils in a PKA-dependent manner and increased the expression of Annexin A1 and CD36, two molecules associated with efferocytosis. Finally, inhibition of endogenous PKA during LPS-induced pleurisy impaired the physiological resolution of inflammation. Taken together, the results suggest that cAMP is involved in the major functions of macrophages, such as nonphlogistic recruitment, reprogramming and efferocytosis, all key processes for inflammation resolution. [ABSTRACT FROM AUTHOR]

Congenital Zika syndrome (CZS) is a cluster of malformation, and the mechanisms that lead it are still unclear. Using hypothesis-driven candidate genes and their function in viral infections, single-nucleotide polymorphisms (SNPs) were genotyped by quantitative polymerase chain reaction in a sample population from Sergipe State, Brazil. This study shows that rs3775291 SNP at Toll-like receptor 3, which triggers type I interferon antiviral responses in mothers infected by Zika virus during pregnancy, is associated with CZS occurrence (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.158-4.148). Moreover, rs1799964 SNP at tumor necrosis factor-α gene in CZS babies is associated with severe microcephaly (OR, 2.63; 95% CI, 1.13-6.21). [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GVHD) is the most serious complication limiting the clinical utility of allogeneic hematopoietic stem cell transplantation (HSCT), in which lymphocytes of donors (graft) are activated in response to the host antigen. This disease is associated with increased inflammatory response through the release of inflammatory mediators such as cytokines, chemokines, and reactive oxygen species (ROS). In this study, we have evaluated the role of ROS in GVHD pathogenesis by treatment of recipient mice with apocynin (apo), an inhibitor of intracellular translocation of cytosolic components of NADPH oxidase complex. The pharmacological blockade of NADPH oxidase resulted in prolonged survival and reduced GVHD clinical score. This reduction in GVHD was associated with reduced levels of ROS and TBARS in target organs of GVHD in apocynin-treated mice at the onset of the mortality phase. These results correlated with reduced intestinal and liver injuries and decreased levels of proinflammatory cytokines and chemokines. Mechanistically, pharmacological blockade of the NADPH oxidase was associated with inhibition of recruitment and accumulation of leukocytes in the target organs. Additionally, the chimerism remained unaffected after treatment with apocynin. Our study demonstrates that ROS plays an important role in mediating GVHD, suggesting that strategies aimed at blocking ROS production may be useful as an adjuvant therapy in patients subjected to bone marrow transplantation. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the role of pentraxin 3 (PTX3), a pivotal component of the innate immune system, in gout. Levels of PTX3 and IL-1b in human samples were evaluated by ELISA. Development of murine gout was evaluated through the levels of cytokines (PTX3, CXCL1, and IL-1b) and neutrophil recruitment into the joint cavity. Phagocytosis of monosodium urate (MSU) crystals and caspase-1 activation were determined by flow cytometer. Acute gout patients showed elevated concentration of PTX3 in plasma and synovial fluid as compared with healthy and osteoarthritic subjects. Moreover, there was a positive correlation between intra-articular PTX3 and IL-1b levels. PTX3 was induced in the periarticular tissue of mice postinjection of MSU crystals. Importantly, Ptx3-deficient mice showed reduced inflammation in response to MSU crystal injection compared with wild-type mice, including reduction of neutrophil recruitment into the joint cavity and IL-1b and CXCL1 production. Interestingly, addition of PTX3 in vitro enhanced MSU crystal phagocytosis by monocytes and resulted in higher production of IL-1b by macrophages. This contribution of PTX3 to the phagocytosis of MSU crystals and consequent production of IL-1b occurred through a mechanism mainly dependent on FcgRIII. Thus, our results suggest that PTX3 acts as a humoral pattern recognition molecule in gout facilitating MSU crystal phagocytosis and contributing to the pathogenesis of gouty arthritis. [ABSTRACT FROM AUTHOR]

The termination of inflammation is governed by endogenous molecules collectively referred to as 'mediators of resolution' of inflammation. There is now strong evidence to suggest that failed resolution may underpin autoimmune and inflammatory diseases and could thus be targeted to decrease inflammation. There are many molecules that have been described as mediators of resolution, and new players are still being continuously discovered. To support the emerging field of 'resolution pharmacology', here we discuss the scientific strategies required to qualify a molecule as a resolution mediator. Systematic definition of the players of resolution, their receptors, and downstream mechanisms remains a necessary knowledge to move the field forward and suggest new targets for the development of novel therapies to treat inflammatory diseases. Highlights A successful inflammatory response tends to resolve in a coordinated series of molecular and cellular events, including the resolving phase of inflammation. Exciting new discoveries have revealed a post-resolution phase of inflammation, composed of a third wave of leukocyte influx that seemingly links innate and adaptive immune systems. Recent discoveries have suggested that failed or impaired resolution of inflammation may underpin the pathogenesis of certain chronic inflammatory diseases, such as inflammatory bowel disease and rheumatoid arthritis. The identification of failed resolution as an underlying cause or contributing factor to certain human inflammatory diseases has brought new exciting therapeutic opportunities for treating inflammation, based on promoting events associated with resolution, rather than simply blocking proinflammatory pathways. Recently, the potential of human translation is reflected by the identification/quantification of proresolving molecules and pathways in humans, and by the pioneering use of human models of inflammation to test the efficacy of proresolving agonists. In order to effectively translate the knowledge of resolution biology into potential new therapeutics for a variety of inflammation-associated diseases, precise definitions of the cellular players, molecular mediators, receptors, and signaling pathways engaged during inflammation resolution are necessary. [ABSTRACT FROM AUTHOR]

Background: Dengue viruses have spread rapidly across tropical regions of the world in recent decades. Today, dengue transmission is observed in the Americas, Southeast Asia, Western Pacific, Africa and in non-endemic areas of the USA and Europe. Dengue is responsible for 16% of travel-related febrile illnesses. Although most prevalent in tropical areas, risk maps indicate that subtropical regions are suitable for transmission. Dengue-control programs in these regions should focus on minimizing virus importation, community engagement, improved vector surveillance and control. Results: We developed a conceptual model for the probability of local introduction and propagation of dengue, comprising disease vulnerability and receptivity, in a temperate area, considering risk factors and social media indicators. Using a rich data set from a temperate area in the south of Brazil (where there is active surveillance of mosquitoes, viruses and human cases), we used a conceptual model as a framework to build two probabilistic models to estimate the probability of initiation and propagation of local dengue transmission. The final models estimated with good accuracy the probabilities of local transmission and propagation, with three and four weeks in advance, respectively. Vulnerability indicators (number of imported cases and dengue virus circulation in mosquitoes) and a receptivity indicator (vector abundance) could be optimally integrated with tweets and temperature data to estimate probability of early local dengue transmission. Conclusions: We demonstrated how vulnerability and receptivity indicators can be integrated into probabilistic models to estimate initiation and propagation of dengue transmission. The models successfully estimate disease risk in different scenarios and periods of the year. We propose a decision model with three different risk levels to assist in the planning of prevention and control measures in temperate regions at risk of dengue introduction. [ABSTRACT FROM AUTHOR]

Neuropathic pain is one of the most important types of chronic pain. It is caused by neuronal damage. Clinical and experimental studies suggest a critical role for neuroimmune interactions in the development of neuropathic pain. In this article, we have shown that the cytoplasmic receptor Nod-like receptor-2, NOD2, and its adaptor-signaling molecule RIPK2 participate in the development of neuropathic pain after peripheral nerve injury (spared nerve injury model). The activation of NOD2 signaling in peripheral macrophage mediates the development of neuropathic pain through the production of pronociceptive cytokines (tumor necrosis factor and IL-1β). This study found that peripheral nerve injury promoted a systemic increase in the NOD2 ligand. These results highlight a previously undetermined role for NOD2 signaling in the development of neuropathic pain, suggesting a new potential target for preventing neuropathic pain. [ABSTRACT FROM AUTHOR]